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Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women
Drug and Alcohol Dependence,
Elsevier Scientific Publishers
28 (1991) 121-128 Ireland Ltd.
121
Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women Robert I. Block”, Roxanna Departments
of Anesthesia”
and Internal
Farinpour”
and Janet A. Schlechteb
Medicine b, College of Medicine.
University
of Iowa, Iowa City. Iowa (U.S.A.)
(Received May 5th, 1990)
To investigate possible effects of chronic marijuana use on reproductive and stress luteinizing hormone, follicle stimulating hormone, prolactin, and cortisol in 93 men and of 23.5 =t 0.4 years. Hormone values were compared among groups of subjects stratified use (frequent, moderate and infrequent; N = 27, 18, and 30, respectively) and non-using use showed no significant effect on hormone concentrations in either men or women. Key words: marijuana;
endocrine; testosterone;
luteinizing hormone; follicle stimulating
Introduction Alterations in endocrine function in conjunction with marijuana use have caused considerable concern. In a widely publicized study, Kolodny, Masters, Kolodner and Toro (1974) reported that testosterone levels were decreased in chronic male marijuana users and that follicle stimulating hormone (FSH) levels were lower in heavier (relative to lighter) users. Cohen (1976) found that chronic marijuana administration to men on a research ward decreased testosterone and luteinizing hormone (LH) and apparently altered FSH as well. In contrast, women have been reported to have increased levels of testosterone and decreased serum prolactin following chronic marijuana use (Dornbush, Kolodny, Bauman and Webster, 19’78; Kolodny, Masters and Johnson, 1979, pp. 337-338). Acute hormonal changes following a single Correspondence
tot Robert I. Block, Department of Anesthesia, College of Medicine, University of Iowa, Iowa City. Iowa 52242, U.S.A.
0376~8716/91/$03.50 0 1991 Elsevier Scientific Publishers Printed and Published in Ireland
hormones, we assayed testosterone, 56 women with a mean ( l S.E.) age according to frequency of marijuana controls (N = 74). Chronic marijuana
hormone; prolactin; cortisol
cannabis dose have also been reported, including lower testosterone and LH levels (Cone, Johnson, Moore and Roache, 1986; Kolodny, Lessin, Toro, Masters and Cohen, 1976; Schaefer, Gunn and Dubowski, 1975) and increased prolactin (Markianos and Stefanis, 1982) in men and decreased prolactin in women tested during the luteal phase of the menstrual cycle (Mendelson, Mello and Ellingboe, 1985). These alterations were noted up to 180 min post-drug. Studies demonstrating hormonal effects of marijuana use, however, are outnumbered by numerous negative reports. Unaltered hormone levels in chronic male marijuana users have been reported for testosterone (Coggins, Swenson, Dawson, Fernandez-Salas, Hernandez-Bolanos, Jiminez-Antillon, Solano, Vinocour and FaerronValdez, 1976; Cushman, 1975; Schaefer, Gunn and Dubowski, 1975), LH (Cushman, 1975; Kolodny, Masters, Kolodner, and Toro, 1974), FSH (Cushman, 1975) and prolactin (Kolodny, Masters, Kolodner and Toro, 1974). Similarly, unaltered hormone levels following chronic marijuana administration to men on a research ward have been reported for testosterone (Hembree, Ireland Ltd.
122
Zeidenberg and Nahas, 1976; Mendelson, Ellingboe, Kuehnle and Mello, 1978; Mendelson, Kuehnle, Ellingboe and Babor, 1974) LH (Hembree, Zeidenberg and Nahas, 1976; Mendelson, Ellingboe, Kuehnle and Mello, 1978), FSH (Hembree, Zeidenberg and Nahas, 1976) and prolactin (Cohen, 1976). A study of chronic female users reported unaltered levels of LH and FSH (Dornbush, Kolodny, Bauman and Webster, 1978). Acute studies have found no changes in testosterone (Cone, Johnson, Moore and Roache, 1986), FSH (Kolodny, Lessin, Toro, Masters and Cohen, 1976) or prolactin (Cone, Johnson, Moore and Roache, 1986; Lemberger, Crabtree, Rowe and Clemens, 1975) levels in men or LH levels in menopausal women (Mendelson, Cristofaro, Ellingboe, Benedikt, and Mello, 1985) following a single cannabis dose. These negative findings are not readily reconciled with the positive reports by differences in dose or duration of cannabis use, so clarification is needed. Further, the existing literature is characterized by three limiting factors. First, in both chronic and acute studies, sample sizes have been small, ranging from 4 to 82 subjects (including controls) with a mean of 22 subjects per study. Studies with larger sample sizes would permit greater confidence in results. Second, although Mendelson, Mello and their colleagues have examined marijuana’s effects on female reproductive function, including its acute effects on LH and prolactin mentioned above (Mello and Mendelson, 1985; Mendelson, Cristofaro, Ellingboe, Benedikt and Mello, 1985; Mendelson, Mello and Ellingboe, 1985) only one study (Dornbush, Kolodny, Bauman and Webster, 1978) has examined effects of chronic marijuana use on women’s reproductive hormones. More generally, as Mello and Mendelson (1985, pp. 162) have observed, ‘... virtually all of the clinical studies of the behavioral and biological effects of marihuana have been carried out in men...‘. With an estimated 47% of marijuana users being female (National Institute on Drug Abuse, 1989, pp. 23), effects of long-term marijuana use on female endocrine function need to be further addressed.
Third, few studies have examined whether frequency of marijuana use modulates the drug’s effects on hormone levels. One study found no systematic relations between testosterone or LH levels and amounts of marijuana smoked by men during 21 days on a research ward (Mendelson, Ellingboe, Kuehnle and Mello, 1978). However, after years of marijuana use, frequent users may conceivably show hormonal changes that less frequent users do not. Concerns about marijuana’s effects on reproductive functions, together with the contradictory data concerning the drug’s effects on concentrations of reproductive hormones and the limiting methodological factors apparent in previous research, led us to conduct the study presented here as part of a larger study assessing cognitive functions in users of marijuana. Volunteers recruited for the cognitive study were given the opportunity to provide blood samples for analysis of four reproductive hormones - testosterone, LH, FSH and prolactin. In addition, cortisol, an adrenal steroid elevated by stress (Asterita, 1985, pp. 87-90), was assessed to control for possible alterations associated with the stress of venipuncture. Hormone levels were analyzed according to frequency of marijuana use. Methods
Study subjects included 149 men and women between the ages of 18 and 42 years. The average age was 23.5 * 0.4 years (mean f SE.). Participants were recruited through local newspaper advertisements. Subjects were briefed about the study and assured confidentiality. Written consent was obtained and compensation was provided for participation. The study was approved by the Institutional Review Board of the University of Iowa. Subjects were in good health as determined by a standard medical questionnaire. One man with diabetes and one woman with an abnormally high testosterone level (8.5 ng/ml) were excluded from the study. To control for possible confounding endocrine alterations associated with mental illness (An-
dreason, 1984, pp. 180-181), psychiatric status was determined by administering the Diagnostic Interview Schedule (DIS) version III-A, a structured psychiatric screening interview intended for use by research staff (Robins and Helzer, 1985). All subjects were free of current major psychiatric disorders. One subject who had a history of bipolar disorder was included in the study since he was not taking any medication and psychiatric symptoms had not been evident in the previous 3 years. No subjects had a history of dependence on illegal drugs other than marijuana. Subjects were asked to classify their average weekly use of marijuana or other cannabis products as ‘not at all’, ‘less than once’, one-four times, five-six times, or seven or more times and to indicate the duration of their use at this frequency. Marijuana users were restricted to individuals who had used marijuana or other cannabis products at least weekly for the last two years. Frequent, moderate and infrequent users were defined as those using marijuana seven or more times weekly, five-six times weekly and one-four times weekly, respectively. For men and women combined, frequent, moderate, and infrequent users reported using marijuana at their indicated frequencies for means of 8.2 f 0.9, 5.8 f 1.0 and 5.9 f 0.9 years, respectively. Non-users were restricted to individuals who had not used marijuana more than twice in their lives. Volunteers completed a questionnaire on which they were asked to report their frequency of use of various categories of abused drugs during their lifetime and during the last month and year. In addition, their use of other medications including oral contraceptives was noted.
sayed using commercial radioimmunoassay kits purchased from Diagnostic Products Corporation (Los Angeles, CA). Prolactin was measured by a commercial double-antibody radioimmunoassay kit obtained from New England Nuclear (Nort Billerica, MA). Cortisol was quantitated by radioimmunoassay using antiserum purchased from American Bio-Systems, Marina, MN and tracer obtained from I.C.N. Bio-Medical, Carson, CA. Mean intra-assay coefficients of variation, determined for all samples, were: testosterone, 11.2 %; LH, 6.8 %; FSH, 5.8 %; prolactin, 7.3 %; cortisol, 7.3 %. Inter-assay coefficients of variation were: testosterone, 20.8 %; LH, 13.9 %; FSH, 8.1 %; prolactin, 13.7 %; cortisol, 11.3 %. Statistical
analysis
Hormone values were submitted to one-way analyses of variance comparing user groups (frequent, moderate, infrequent and non-users). Men and women were analyzed separately. Additional one-way analyses of variance were performed to control for possible confounding factors. First, to control for possible eonfounding due to oral contraceptive use, females taking oral contraceptives (34%) were analyzed separately from those who were not (66%). Second, the possibility of confounding circadian variations in levels of hormones, particularly cortisol, was examined by analyzing data from morning venipunctures (0900 h-1200 h, 26%) and afternoon venipunctures (1200 h-1600 h, 74%) separately. Last, possible confounding age effects (Kolodny, Masters and Johnson, 1979, pp. 104-108) were examined by comparing ages of subjects in the four user groups. Results
Sample collection procedure
Blood was obtained by venipuncture and collection time was noted for each sample. Serum was stored at - 20°C until assayed. The samples were analyzed in two assays in the Endocrinology Laboratory at the University of Iowa. Hormone
analysis
Serum testosterone,
LH and FSH were as-
Mean ages of subjects in the four groups are shown in Table I. The user groups did not differ significantly in age. Medical conditions reported by at least 590 of the subjects included tonsillectomy (16.1 %), mononucleosis (13.4 %), broken bones (8.7 %), ‘strep throat’ (8.7 %), heart murmur (5.4 %) and bladder infection (5.4 %). Oral contraceptive use
124 MEN
Table I. Ages.
HORMONE
User group
Women
Men
0
n
Frequent Moderate Infrequent Non
N
Age
22 13 23 35
25.1 23.0 24.3 24.6
f f f i
1.1 1.1 1.3 1.1
iv
Age
5 5 7 39
24.6 23.6 20.9 21.7
zt f f f
TEST PROLAC
2.7 2.5 0.7 0.6
Note: Means * S.E. are shown.
was reported by 34 90 of the women. Use of medications other than oral contraceptives was noted for 11 % of the subjects. Antihistamines, bronchodilators, antibiotics and aeetaminophen were most commonly used. The percentages of subjects within each group having experience with drugs of abuse other than marijuana in their lifetime and in the previous month are shown in Table II. Among all groups, alcohol was the only drug other than marijuana that was commonly used within the last month. Frequent marijuana users had the most experience with other drugs in their lifetime. Cocaine, amphetamines and psychedelics
Table II.
Percentage
Drug
FREOUENT
MODERATE
INFREQUENT USER
BRUW
Fig. 1. Mean testosterone and prolactin levels for male marijuana user groups. TEST = testosterone and PROLAC = prolactin.
were the illicit drugs with which they had the most experience. Non-users had almost no experience with drugs other than alcohol. Mean testosterone and prolactin levels are shown in Figs. 1 and 2 for men and women, respectively. Individual testosterone values for
of drug use in lifetime and previous month.
Marijuana user group Frequent
AIC. LSD Other psych. Cocaine Amphet. Quaal. Barb. Tranq. Heroin Other narcotics PCP Amyl/Butyl nitrites
NON
Moderate
Infrequent
Non
Life
Mon.
Life
Mon.
Life
Mon.
Life
Mon.
100.0 81.5 88.9 96.3 88.9 40.7 44.4 63.0 18.5 55.6 18.5
92.6 11.1 14.8 29.6 18.5 0.0 0.0 0.0 0.0 11.1 3.7
100.0 73.7 52.6 73.7 68.4 36.8 10.5 36.8 5.3 47.4 10.5
100.0 21.1 5.3 15.8 15.8 0.0 0.0 0.0 0.0 5.3 0.0
100.0 70.0 80.0 83.3 60.0 20.0 13.3 33.3 6.7 26.7 6.7
96.7 13.3 20.0 20.0 6.7 0.0 0.0 0.0 0.0 3.3 0.0
97.3 0.0 1.4 2.7 6.8 0.0 0.0 4.1 0.0 2.7 0.0
80.8 0.0 0.0 0.0 0.0 0.0 0.0 1.6 0.0 0.0 0.0
48.2
0.0
42.1
0.0
43.3
6.7
2.7
0.0
Note: Mon. = previous month, Ale. = alcohol, Other psych. = other psychedelics, Amphet. = amphetamines, qualone (Quaaludes), Barb. = barbiturates, Tranq. = tranquilizers and PCP = phencyclidine.
Quaal. = metha-
MEN
WOMEN
25
T
l-
HORMONE a
TEST 20
IS e . 2 E
10
5
0 NON
INFREQUENT USER
MODERATE
NON
FREQUENT
INFREQUENT
MODERATE
FREWENT
USER 6ROU’
6Row
Fig. 2. Mean testosterone and prolactin levels for female marijuana user groups. TEST = testosterone and PROLAC = prolactin.
Fig. 3. Mean FSH and LH levels for male marijuana user groups. FSH = follicle stimulating hormone and LH = luteinizing hormone.
men and women ranged from 0.2 to 15.3 nglml and 0.0 to 4.5 nglml, respectively, with 10.8% of the men and 5.4% of the women falling outside normal laboratory ranges (men, > 3 nglml; women, < 1 ng/ml). Individual prolactin values for men and women ranged from 2.3 to 28.9 ng/ml and 2.3 to 32.7 ng/ml, respectively. Values exceeding normal range (C 25 nglml) were found in 1.1 % of the men and 1.8 % of the women. Mean FSH and LH levels are shown in Figs. 3 and 4 for men and women. Individual LH values ranged from 3.2 to 30.8 mI.U./ml for men and 0.0 to 39.7 mI.U./ml for women, with values of 1.1 % of the men and 1.8 % of the women exceeding normal ranges (men, c 25 mI.U./ml; women, < 38 mI.U./ml). Individual FSH values ranged from 1.3 to 21.2 mI.U./ml for men and 0.9 to 15.6 mI.U./ml for women, with values of 1.1% of the men and 0.0% of the women exceeding normal range (c 20 mI.U./ml). Mean cortisol values for morning and afternoon venipunctures are shown separately in Table III. Individual values for cortisol ranged from 5.1 to 65.0 pgldl for men and 4.8 to 52.9 pgldl for women. Analysis of female marijuana user groups demonstrated no significant intergroup differ-
ences in testosterone, LH, FSH, prolactin and cortisol levels. Similarly, no differences for any of the five hormones were found among male user groups. The additional analyses of oral contraceptive use demonstrated no significant hormonal differences among marijuana user groups either for women who were not using oral contracep-
WOMEN 25 HORNONE
15
f .
2
10
E
5
n NON
INFREQUENT
MODERATE
FRFOUFNT
USER BROW
Fig. 4. Mean FSH and LH levels for female marijuana user groups. FSH = follicle stimulating hormone and LH = luteinizing hormone.
126
Table
III.
Cortisol
levels (pgidl). Women
Men
User group
16.2 f 23.6 zt 19.6 * 17.9 l
Frequent Moderate Infrequent Non Note: Means
l
S.E. are shown
1.4 5.2 4.8 1.6 separately
17.8 f 17.6 + 20.1 f 15.1 l
Afternoon
Morning
Afternoon
Morning
2.3 2.4
7.9 f 18.9’
2.9 1.1
35.s* 26.2 * 13.4
for venipunctures
3.1
done in the morning
10.9 f 1.3 22.8 f 5.2 21.5 f 3.2 16.9 + 1.4 (0900 h-1200
h) and afternoon
(1200 h-
1600 h). *N= 1.
tives or for those reporting oral use. The separate analyses of data venipunctures and afternoon found no differences among user mone levels.
contraceptive from morning venipunctures groups in hor-
Discussion
The present study demonstrates an absence of significant hormonal changes in chronic male marijuana users. Our findings are at variance with widely publicized findings of Kolodny, Masters, Kolodner and Toro (1974) who found decreased testosterone levels in chronic male marijuana users and support findings of others (Coggins, Swenson, Dawson, Fernandez-Salas, Hernandez-Bolanos, Jiminez-Antillon, Solano, Vinocour and Faerron-Valdez, 1976; Cushman, 1975; Schaefer, Gunn and Dubowski, 1975), who did not observe such decreases. The findings of Kolodny and colleagues continue today to be widely disseminated in informational literature provided to the general public despite their lack of reproducibility. Kolodny and colleagues found mean testosterone levels of 416 f 34 ng/lOO ml in 20 men who used marijuana at least four times weekly for at least 6 months compared to 742 f ‘29 ng/lOO ml in 20 non-users. In addition, heavier marijuana users were found to have lower levels of testosterone than lighter users (309 =t 34 compared to 503 f 40 ng/lOO ml). In frequency of use, the subjects studied by Kolodny and col-
leagues appear comparable to our frequent users and our subjects had been using marijuana for more years on average than those of Kolodny and colleagues. The sample size of Kolodny and colleagues was relatively small considering individual variations in testosterone concentrations. Whether sample size, differences in subjects’ use of other drugs, or other procedural differences between their study and ours explain the discrepancy in results is unclear. In any case, average testosterone levels in the marijuana users studied by Kolodny and colleagues fell within their laboratory’s normal range (380-980 ng/lOO ml), so the decrease they observed may have had greater statistical than clinical significance. In women, as in men, we found no effect of chronic marijuana use on testosterone, LH, FSH, prolactin and cortisol. This lack of an effeet in the present study is in conflict with the one report available concerning effects of chronic marijuana use on women’s endocrine hormone levels. Dornbush, Kolodny, Bauman and Webster (1978) reported increased levels of testosterone and lowered levels of prolactin in chronic female marijuana users. Why we obtained different results is, again, unclear. The present study provides additional informative data concerning women’s endocrine hormone levels following chronic marijuana use, an area that has clearly been under-investigated. No hormonal effects of chronic marijuana use were detected either for the women who were using oral contraceptives or for those who were
127
not. Thus, the absence of hormonal effects of chronic marijuana use on women could not be attributed to confounding or increased variability due to mixing together data of oral contraceptive users and non-users. Similarly, separate analyses of data from the morning and afternoon venipunctures found no differences among marijuana user groups in hormone levels, so circadian variations did not mask marijuana’s effects. The marijuana user groups showed no differences in mean cortisol levels, suggesting that they were equally affected by any stress due to the venipuncture procedure, i.e. stress did not mask marijuana’s effects on endocrine hormone levels. It is conceivable that effects of chronic marijuana use may have been masked by a confounding variable that we could not analyze because we obtained only one blood sample from each subject in the present study: Many hormones are not secreted continuously and inter- and intraindividual variation in patterns of episodic secretion may have increased variability in our data, making effects of chronic marijuana use harder to detect. However, Mendelson, Ellingboe, Kuehnle and Mello (1978) found no systematic effects of a 21-day period of marijuana use on men’s integrated testosterone and LH levels measured using an indwelling intravenous catheter for continuous blood sampling. The study of Mendelson and colleagues involved 13 subjects. In the present study, we chose to obtain more limited data from each individual in order to attain a larger sample size. Our finding that chronic marijuana use did not alter endocrine hormone levels of men or women in no way diminishes concerns about other adverse physiological and psychological effects of marijuana use, including possible effects on reproductive function. For example, chronic marijuana use by mothers before and during pregnancy was reportedly associated with neurobehavioral changes in their newborn, compared to the newborn of non-users (Fried, 1980; Fried, 1982); and offspring of women who chronically used marijuana during pregnancy, compared to those of non-users, had lower birth weights and were more likely to have abnormalities compatible with the fetal alcohol syndrome
(Hingson, Alpert, Day, Dooling, Kayne, Morelock, Oppenheimer and Zuckerman, 1982). Other studies have reported decreased birth weight and length in offspring of marijuanausing mothers identified by urine assays (Zuckerman, Frank, Hingson, Amaro, Levenson, Kayne, Parker, Vinci, Aboagye, Fried, Cabral, Timperi and Bauchner, 1989) and an increased frequency of premature births among women who chronically used marijuana during pregnancy (Gibson, Baghurst and Colley, 1983). There are concerns, too, about marijuana’s effects on the male reproductive system. In one study, chronic hashish users, compared to controls, showed abnormalities of sperm heads (Issidorides, 1979). In another, 35% of chronic marijuana users showed oligospermia (Kolodny, Masters, Kolodner and Toro, 1974). Volunteers on a research ward who smoked high doses of marijuana showed decreased sperm motility during smoking and decreased sperm concentration, sperm count and percentage of sperm with normal morphology after cessation of smoking (Hembree, Nahas, Zeidenberg and Huang, 1979; Hembree, Zeidenberg and Nahas, 1976). Some of these studies reporting adverse effects of marijuana use on reproductive function need replication, Cumulatively, however, they provide reasons for concern and significant clinical information which physicians may want to communicate to their many marijuana-using patients. In the present study, the results were less worrisome: we found no effects of marijuana use on endocrine hormone levels in a substantial sample of men and women representing three frequencies of chronic marijuana use typical of usage patterns in the general population. This, too, provides significant clinical information which may be helpful to physicians interested in providing their patients with a balanced and accurate picture of the health consequences of marijuana use. Acknowledgements
Thanks are due to Sara Farnham, Kathleen Braverman, Joanne West, Paul Muhle, Margrieta Delle and Robert Fleming for their assistance with the research. This study was sup-
128
ported in part by grant thor from the National and by grant RR00059 Center, University of of Research Resources, Health.
DA03988 to the first auInstitute on Drug Abuse to the Clinical Research Iowa from the Division National Institutes of
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Salas, A., Hernandez-Bolanos, J., Jiminez-Antillon, C.F., Solano, J.R., Vinocour, R. and Faerron-Valdez, F. (1976) Health status of chronic heavy cannabis users. Ann. N.Y. Acad. Sci. 282, 148. Cohen, S. (1976) The 94-day cannabis study. Ann. N.Y. Acad. Sci. 282, 211. Cone, E.J., Johnson, R.E., Moore, J.D. and Roache, J.D. (1986) Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects. Pharmacol., Biochem. Behav. 24, 1’749. Cushman, P. (1975) Plasma testosterone levels in healthy male marijuana smokers. Am. J. Drug Alcohol Abuse 2, 269. Dornbush, R.L., Kolodny, R.C., Bauman, J.E. and Webster, SK. (1978) Human female chronic marijuana use and endocrine functioning. Sot. Neurosci. Abstr. 4, 490. Fried, P.A. (1980) Marihuana use by pregnant women: Neurobehavioral effects in neonates. Drug Alcohol Depend. 6, 415. Fried, P.A. (1982) Marihuana use by pregnant women and effects on offspring: An update. Neurobehav. Toxicol. Teratol. 4, 451. Gibson, G.T., Baghurst,P.A. and Colley, D.P. (1983) Maternal alcohol, tobacco and cannabis consumption and the outcome 23, 15. Hembree, Huang,
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Elsevier Scientific Publishers
28 (1991) 121-128 Ireland Ltd.
121
Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women Robert I. Block”, Roxanna Departments
of Anesthesia”
and Internal
Farinpour”
and Janet A. Schlechteb
Medicine b, College of Medicine.
University
of Iowa, Iowa City. Iowa (U.S.A.)
(Received May 5th, 1990)
To investigate possible effects of chronic marijuana use on reproductive and stress luteinizing hormone, follicle stimulating hormone, prolactin, and cortisol in 93 men and of 23.5 =t 0.4 years. Hormone values were compared among groups of subjects stratified use (frequent, moderate and infrequent; N = 27, 18, and 30, respectively) and non-using use showed no significant effect on hormone concentrations in either men or women. Key words: marijuana;
endocrine; testosterone;
luteinizing hormone; follicle stimulating
Introduction Alterations in endocrine function in conjunction with marijuana use have caused considerable concern. In a widely publicized study, Kolodny, Masters, Kolodner and Toro (1974) reported that testosterone levels were decreased in chronic male marijuana users and that follicle stimulating hormone (FSH) levels were lower in heavier (relative to lighter) users. Cohen (1976) found that chronic marijuana administration to men on a research ward decreased testosterone and luteinizing hormone (LH) and apparently altered FSH as well. In contrast, women have been reported to have increased levels of testosterone and decreased serum prolactin following chronic marijuana use (Dornbush, Kolodny, Bauman and Webster, 19’78; Kolodny, Masters and Johnson, 1979, pp. 337-338). Acute hormonal changes following a single Correspondence
tot Robert I. Block, Department of Anesthesia, College of Medicine, University of Iowa, Iowa City. Iowa 52242, U.S.A.
0376~8716/91/$03.50 0 1991 Elsevier Scientific Publishers Printed and Published in Ireland
hormones, we assayed testosterone, 56 women with a mean ( l S.E.) age according to frequency of marijuana controls (N = 74). Chronic marijuana
hormone; prolactin; cortisol
cannabis dose have also been reported, including lower testosterone and LH levels (Cone, Johnson, Moore and Roache, 1986; Kolodny, Lessin, Toro, Masters and Cohen, 1976; Schaefer, Gunn and Dubowski, 1975) and increased prolactin (Markianos and Stefanis, 1982) in men and decreased prolactin in women tested during the luteal phase of the menstrual cycle (Mendelson, Mello and Ellingboe, 1985). These alterations were noted up to 180 min post-drug. Studies demonstrating hormonal effects of marijuana use, however, are outnumbered by numerous negative reports. Unaltered hormone levels in chronic male marijuana users have been reported for testosterone (Coggins, Swenson, Dawson, Fernandez-Salas, Hernandez-Bolanos, Jiminez-Antillon, Solano, Vinocour and FaerronValdez, 1976; Cushman, 1975; Schaefer, Gunn and Dubowski, 1975), LH (Cushman, 1975; Kolodny, Masters, Kolodner, and Toro, 1974), FSH (Cushman, 1975) and prolactin (Kolodny, Masters, Kolodner and Toro, 1974). Similarly, unaltered hormone levels following chronic marijuana administration to men on a research ward have been reported for testosterone (Hembree, Ireland Ltd.
122
Zeidenberg and Nahas, 1976; Mendelson, Ellingboe, Kuehnle and Mello, 1978; Mendelson, Kuehnle, Ellingboe and Babor, 1974) LH (Hembree, Zeidenberg and Nahas, 1976; Mendelson, Ellingboe, Kuehnle and Mello, 1978), FSH (Hembree, Zeidenberg and Nahas, 1976) and prolactin (Cohen, 1976). A study of chronic female users reported unaltered levels of LH and FSH (Dornbush, Kolodny, Bauman and Webster, 1978). Acute studies have found no changes in testosterone (Cone, Johnson, Moore and Roache, 1986), FSH (Kolodny, Lessin, Toro, Masters and Cohen, 1976) or prolactin (Cone, Johnson, Moore and Roache, 1986; Lemberger, Crabtree, Rowe and Clemens, 1975) levels in men or LH levels in menopausal women (Mendelson, Cristofaro, Ellingboe, Benedikt, and Mello, 1985) following a single cannabis dose. These negative findings are not readily reconciled with the positive reports by differences in dose or duration of cannabis use, so clarification is needed. Further, the existing literature is characterized by three limiting factors. First, in both chronic and acute studies, sample sizes have been small, ranging from 4 to 82 subjects (including controls) with a mean of 22 subjects per study. Studies with larger sample sizes would permit greater confidence in results. Second, although Mendelson, Mello and their colleagues have examined marijuana’s effects on female reproductive function, including its acute effects on LH and prolactin mentioned above (Mello and Mendelson, 1985; Mendelson, Cristofaro, Ellingboe, Benedikt and Mello, 1985; Mendelson, Mello and Ellingboe, 1985) only one study (Dornbush, Kolodny, Bauman and Webster, 1978) has examined effects of chronic marijuana use on women’s reproductive hormones. More generally, as Mello and Mendelson (1985, pp. 162) have observed, ‘... virtually all of the clinical studies of the behavioral and biological effects of marihuana have been carried out in men...‘. With an estimated 47% of marijuana users being female (National Institute on Drug Abuse, 1989, pp. 23), effects of long-term marijuana use on female endocrine function need to be further addressed.
Third, few studies have examined whether frequency of marijuana use modulates the drug’s effects on hormone levels. One study found no systematic relations between testosterone or LH levels and amounts of marijuana smoked by men during 21 days on a research ward (Mendelson, Ellingboe, Kuehnle and Mello, 1978). However, after years of marijuana use, frequent users may conceivably show hormonal changes that less frequent users do not. Concerns about marijuana’s effects on reproductive functions, together with the contradictory data concerning the drug’s effects on concentrations of reproductive hormones and the limiting methodological factors apparent in previous research, led us to conduct the study presented here as part of a larger study assessing cognitive functions in users of marijuana. Volunteers recruited for the cognitive study were given the opportunity to provide blood samples for analysis of four reproductive hormones - testosterone, LH, FSH and prolactin. In addition, cortisol, an adrenal steroid elevated by stress (Asterita, 1985, pp. 87-90), was assessed to control for possible alterations associated with the stress of venipuncture. Hormone levels were analyzed according to frequency of marijuana use. Methods
Study subjects included 149 men and women between the ages of 18 and 42 years. The average age was 23.5 * 0.4 years (mean f SE.). Participants were recruited through local newspaper advertisements. Subjects were briefed about the study and assured confidentiality. Written consent was obtained and compensation was provided for participation. The study was approved by the Institutional Review Board of the University of Iowa. Subjects were in good health as determined by a standard medical questionnaire. One man with diabetes and one woman with an abnormally high testosterone level (8.5 ng/ml) were excluded from the study. To control for possible confounding endocrine alterations associated with mental illness (An-
dreason, 1984, pp. 180-181), psychiatric status was determined by administering the Diagnostic Interview Schedule (DIS) version III-A, a structured psychiatric screening interview intended for use by research staff (Robins and Helzer, 1985). All subjects were free of current major psychiatric disorders. One subject who had a history of bipolar disorder was included in the study since he was not taking any medication and psychiatric symptoms had not been evident in the previous 3 years. No subjects had a history of dependence on illegal drugs other than marijuana. Subjects were asked to classify their average weekly use of marijuana or other cannabis products as ‘not at all’, ‘less than once’, one-four times, five-six times, or seven or more times and to indicate the duration of their use at this frequency. Marijuana users were restricted to individuals who had used marijuana or other cannabis products at least weekly for the last two years. Frequent, moderate and infrequent users were defined as those using marijuana seven or more times weekly, five-six times weekly and one-four times weekly, respectively. For men and women combined, frequent, moderate, and infrequent users reported using marijuana at their indicated frequencies for means of 8.2 f 0.9, 5.8 f 1.0 and 5.9 f 0.9 years, respectively. Non-users were restricted to individuals who had not used marijuana more than twice in their lives. Volunteers completed a questionnaire on which they were asked to report their frequency of use of various categories of abused drugs during their lifetime and during the last month and year. In addition, their use of other medications including oral contraceptives was noted.
sayed using commercial radioimmunoassay kits purchased from Diagnostic Products Corporation (Los Angeles, CA). Prolactin was measured by a commercial double-antibody radioimmunoassay kit obtained from New England Nuclear (Nort Billerica, MA). Cortisol was quantitated by radioimmunoassay using antiserum purchased from American Bio-Systems, Marina, MN and tracer obtained from I.C.N. Bio-Medical, Carson, CA. Mean intra-assay coefficients of variation, determined for all samples, were: testosterone, 11.2 %; LH, 6.8 %; FSH, 5.8 %; prolactin, 7.3 %; cortisol, 7.3 %. Inter-assay coefficients of variation were: testosterone, 20.8 %; LH, 13.9 %; FSH, 8.1 %; prolactin, 13.7 %; cortisol, 11.3 %. Statistical
analysis
Hormone values were submitted to one-way analyses of variance comparing user groups (frequent, moderate, infrequent and non-users). Men and women were analyzed separately. Additional one-way analyses of variance were performed to control for possible confounding factors. First, to control for possible eonfounding due to oral contraceptive use, females taking oral contraceptives (34%) were analyzed separately from those who were not (66%). Second, the possibility of confounding circadian variations in levels of hormones, particularly cortisol, was examined by analyzing data from morning venipunctures (0900 h-1200 h, 26%) and afternoon venipunctures (1200 h-1600 h, 74%) separately. Last, possible confounding age effects (Kolodny, Masters and Johnson, 1979, pp. 104-108) were examined by comparing ages of subjects in the four user groups. Results
Sample collection procedure
Blood was obtained by venipuncture and collection time was noted for each sample. Serum was stored at - 20°C until assayed. The samples were analyzed in two assays in the Endocrinology Laboratory at the University of Iowa. Hormone
analysis
Serum testosterone,
LH and FSH were as-
Mean ages of subjects in the four groups are shown in Table I. The user groups did not differ significantly in age. Medical conditions reported by at least 590 of the subjects included tonsillectomy (16.1 %), mononucleosis (13.4 %), broken bones (8.7 %), ‘strep throat’ (8.7 %), heart murmur (5.4 %) and bladder infection (5.4 %). Oral contraceptive use
124 MEN
Table I. Ages.
HORMONE
User group
Women
Men
0
n
Frequent Moderate Infrequent Non
N
Age
22 13 23 35
25.1 23.0 24.3 24.6
f f f i
1.1 1.1 1.3 1.1
iv
Age
5 5 7 39
24.6 23.6 20.9 21.7
zt f f f
TEST PROLAC
2.7 2.5 0.7 0.6
Note: Means * S.E. are shown.
was reported by 34 90 of the women. Use of medications other than oral contraceptives was noted for 11 % of the subjects. Antihistamines, bronchodilators, antibiotics and aeetaminophen were most commonly used. The percentages of subjects within each group having experience with drugs of abuse other than marijuana in their lifetime and in the previous month are shown in Table II. Among all groups, alcohol was the only drug other than marijuana that was commonly used within the last month. Frequent marijuana users had the most experience with other drugs in their lifetime. Cocaine, amphetamines and psychedelics
Table II.
Percentage
Drug
FREOUENT
MODERATE
INFREQUENT USER
BRUW
Fig. 1. Mean testosterone and prolactin levels for male marijuana user groups. TEST = testosterone and PROLAC = prolactin.
were the illicit drugs with which they had the most experience. Non-users had almost no experience with drugs other than alcohol. Mean testosterone and prolactin levels are shown in Figs. 1 and 2 for men and women, respectively. Individual testosterone values for
of drug use in lifetime and previous month.
Marijuana user group Frequent
AIC. LSD Other psych. Cocaine Amphet. Quaal. Barb. Tranq. Heroin Other narcotics PCP Amyl/Butyl nitrites
NON
Moderate
Infrequent
Non
Life
Mon.
Life
Mon.
Life
Mon.
Life
Mon.
100.0 81.5 88.9 96.3 88.9 40.7 44.4 63.0 18.5 55.6 18.5
92.6 11.1 14.8 29.6 18.5 0.0 0.0 0.0 0.0 11.1 3.7
100.0 73.7 52.6 73.7 68.4 36.8 10.5 36.8 5.3 47.4 10.5
100.0 21.1 5.3 15.8 15.8 0.0 0.0 0.0 0.0 5.3 0.0
100.0 70.0 80.0 83.3 60.0 20.0 13.3 33.3 6.7 26.7 6.7
96.7 13.3 20.0 20.0 6.7 0.0 0.0 0.0 0.0 3.3 0.0
97.3 0.0 1.4 2.7 6.8 0.0 0.0 4.1 0.0 2.7 0.0
80.8 0.0 0.0 0.0 0.0 0.0 0.0 1.6 0.0 0.0 0.0
48.2
0.0
42.1
0.0
43.3
6.7
2.7
0.0
Note: Mon. = previous month, Ale. = alcohol, Other psych. = other psychedelics, Amphet. = amphetamines, qualone (Quaaludes), Barb. = barbiturates, Tranq. = tranquilizers and PCP = phencyclidine.
Quaal. = metha-
MEN
WOMEN
25
T
l-
HORMONE a
TEST 20
IS e . 2 E
10
5
0 NON
INFREQUENT USER
MODERATE
NON
FREQUENT
INFREQUENT
MODERATE
FREWENT
USER 6ROU’
6Row
Fig. 2. Mean testosterone and prolactin levels for female marijuana user groups. TEST = testosterone and PROLAC = prolactin.
Fig. 3. Mean FSH and LH levels for male marijuana user groups. FSH = follicle stimulating hormone and LH = luteinizing hormone.
men and women ranged from 0.2 to 15.3 nglml and 0.0 to 4.5 nglml, respectively, with 10.8% of the men and 5.4% of the women falling outside normal laboratory ranges (men, > 3 nglml; women, < 1 ng/ml). Individual prolactin values for men and women ranged from 2.3 to 28.9 ng/ml and 2.3 to 32.7 ng/ml, respectively. Values exceeding normal range (C 25 nglml) were found in 1.1 % of the men and 1.8 % of the women. Mean FSH and LH levels are shown in Figs. 3 and 4 for men and women. Individual LH values ranged from 3.2 to 30.8 mI.U./ml for men and 0.0 to 39.7 mI.U./ml for women, with values of 1.1 % of the men and 1.8 % of the women exceeding normal ranges (men, c 25 mI.U./ml; women, < 38 mI.U./ml). Individual FSH values ranged from 1.3 to 21.2 mI.U./ml for men and 0.9 to 15.6 mI.U./ml for women, with values of 1.1% of the men and 0.0% of the women exceeding normal range (c 20 mI.U./ml). Mean cortisol values for morning and afternoon venipunctures are shown separately in Table III. Individual values for cortisol ranged from 5.1 to 65.0 pgldl for men and 4.8 to 52.9 pgldl for women. Analysis of female marijuana user groups demonstrated no significant intergroup differ-
ences in testosterone, LH, FSH, prolactin and cortisol levels. Similarly, no differences for any of the five hormones were found among male user groups. The additional analyses of oral contraceptive use demonstrated no significant hormonal differences among marijuana user groups either for women who were not using oral contracep-
WOMEN 25 HORNONE
15
f .
2
10
E
5
n NON
INFREQUENT
MODERATE
FRFOUFNT
USER BROW
Fig. 4. Mean FSH and LH levels for female marijuana user groups. FSH = follicle stimulating hormone and LH = luteinizing hormone.
126
Table
III.
Cortisol
levels (pgidl). Women
Men
User group
16.2 f 23.6 zt 19.6 * 17.9 l
Frequent Moderate Infrequent Non Note: Means
l
S.E. are shown
1.4 5.2 4.8 1.6 separately
17.8 f 17.6 + 20.1 f 15.1 l
Afternoon
Morning
Afternoon
Morning
2.3 2.4
7.9 f 18.9’
2.9 1.1
35.s* 26.2 * 13.4
for venipunctures
3.1
done in the morning
10.9 f 1.3 22.8 f 5.2 21.5 f 3.2 16.9 + 1.4 (0900 h-1200
h) and afternoon
(1200 h-
1600 h). *N= 1.
tives or for those reporting oral use. The separate analyses of data venipunctures and afternoon found no differences among user mone levels.
contraceptive from morning venipunctures groups in hor-
Discussion
The present study demonstrates an absence of significant hormonal changes in chronic male marijuana users. Our findings are at variance with widely publicized findings of Kolodny, Masters, Kolodner and Toro (1974) who found decreased testosterone levels in chronic male marijuana users and support findings of others (Coggins, Swenson, Dawson, Fernandez-Salas, Hernandez-Bolanos, Jiminez-Antillon, Solano, Vinocour and Faerron-Valdez, 1976; Cushman, 1975; Schaefer, Gunn and Dubowski, 1975), who did not observe such decreases. The findings of Kolodny and colleagues continue today to be widely disseminated in informational literature provided to the general public despite their lack of reproducibility. Kolodny and colleagues found mean testosterone levels of 416 f 34 ng/lOO ml in 20 men who used marijuana at least four times weekly for at least 6 months compared to 742 f ‘29 ng/lOO ml in 20 non-users. In addition, heavier marijuana users were found to have lower levels of testosterone than lighter users (309 =t 34 compared to 503 f 40 ng/lOO ml). In frequency of use, the subjects studied by Kolodny and col-
leagues appear comparable to our frequent users and our subjects had been using marijuana for more years on average than those of Kolodny and colleagues. The sample size of Kolodny and colleagues was relatively small considering individual variations in testosterone concentrations. Whether sample size, differences in subjects’ use of other drugs, or other procedural differences between their study and ours explain the discrepancy in results is unclear. In any case, average testosterone levels in the marijuana users studied by Kolodny and colleagues fell within their laboratory’s normal range (380-980 ng/lOO ml), so the decrease they observed may have had greater statistical than clinical significance. In women, as in men, we found no effect of chronic marijuana use on testosterone, LH, FSH, prolactin and cortisol. This lack of an effeet in the present study is in conflict with the one report available concerning effects of chronic marijuana use on women’s endocrine hormone levels. Dornbush, Kolodny, Bauman and Webster (1978) reported increased levels of testosterone and lowered levels of prolactin in chronic female marijuana users. Why we obtained different results is, again, unclear. The present study provides additional informative data concerning women’s endocrine hormone levels following chronic marijuana use, an area that has clearly been under-investigated. No hormonal effects of chronic marijuana use were detected either for the women who were using oral contraceptives or for those who were
127
not. Thus, the absence of hormonal effects of chronic marijuana use on women could not be attributed to confounding or increased variability due to mixing together data of oral contraceptive users and non-users. Similarly, separate analyses of data from the morning and afternoon venipunctures found no differences among marijuana user groups in hormone levels, so circadian variations did not mask marijuana’s effects. The marijuana user groups showed no differences in mean cortisol levels, suggesting that they were equally affected by any stress due to the venipuncture procedure, i.e. stress did not mask marijuana’s effects on endocrine hormone levels. It is conceivable that effects of chronic marijuana use may have been masked by a confounding variable that we could not analyze because we obtained only one blood sample from each subject in the present study: Many hormones are not secreted continuously and inter- and intraindividual variation in patterns of episodic secretion may have increased variability in our data, making effects of chronic marijuana use harder to detect. However, Mendelson, Ellingboe, Kuehnle and Mello (1978) found no systematic effects of a 21-day period of marijuana use on men’s integrated testosterone and LH levels measured using an indwelling intravenous catheter for continuous blood sampling. The study of Mendelson and colleagues involved 13 subjects. In the present study, we chose to obtain more limited data from each individual in order to attain a larger sample size. Our finding that chronic marijuana use did not alter endocrine hormone levels of men or women in no way diminishes concerns about other adverse physiological and psychological effects of marijuana use, including possible effects on reproductive function. For example, chronic marijuana use by mothers before and during pregnancy was reportedly associated with neurobehavioral changes in their newborn, compared to the newborn of non-users (Fried, 1980; Fried, 1982); and offspring of women who chronically used marijuana during pregnancy, compared to those of non-users, had lower birth weights and were more likely to have abnormalities compatible with the fetal alcohol syndrome
(Hingson, Alpert, Day, Dooling, Kayne, Morelock, Oppenheimer and Zuckerman, 1982). Other studies have reported decreased birth weight and length in offspring of marijuanausing mothers identified by urine assays (Zuckerman, Frank, Hingson, Amaro, Levenson, Kayne, Parker, Vinci, Aboagye, Fried, Cabral, Timperi and Bauchner, 1989) and an increased frequency of premature births among women who chronically used marijuana during pregnancy (Gibson, Baghurst and Colley, 1983). There are concerns, too, about marijuana’s effects on the male reproductive system. In one study, chronic hashish users, compared to controls, showed abnormalities of sperm heads (Issidorides, 1979). In another, 35% of chronic marijuana users showed oligospermia (Kolodny, Masters, Kolodner and Toro, 1974). Volunteers on a research ward who smoked high doses of marijuana showed decreased sperm motility during smoking and decreased sperm concentration, sperm count and percentage of sperm with normal morphology after cessation of smoking (Hembree, Nahas, Zeidenberg and Huang, 1979; Hembree, Zeidenberg and Nahas, 1976). Some of these studies reporting adverse effects of marijuana use on reproductive function need replication, Cumulatively, however, they provide reasons for concern and significant clinical information which physicians may want to communicate to their many marijuana-using patients. In the present study, the results were less worrisome: we found no effects of marijuana use on endocrine hormone levels in a substantial sample of men and women representing three frequencies of chronic marijuana use typical of usage patterns in the general population. This, too, provides significant clinical information which may be helpful to physicians interested in providing their patients with a balanced and accurate picture of the health consequences of marijuana use. Acknowledgements
Thanks are due to Sara Farnham, Kathleen Braverman, Joanne West, Paul Muhle, Margrieta Delle and Robert Fleming for their assistance with the research. This study was sup-
128
ported in part by grant thor from the National and by grant RR00059 Center, University of of Research Resources, Health.
DA03988 to the first auInstitute on Drug Abuse to the Clinical Research Iowa from the Division National Institutes of
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